Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis

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Abstract

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%–40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

Authors

Andrea Fava, Jill Buyon, Laurence Magder, Jeff Hodgin, Avi Rosenberg, Dawit S. Demeke, Deepak A. Rao, Arnon Arazi, Alessandra Ida Celia, Chaim Putterman, Jennifer H. Anolik, Jennifer Barnas, Maria Dall’Era, David Wofsy, Richard Furie, Diane Kamen, Kenneth Kalunian, Judith A. James, Joel Guthridge, Mohamed G. Atta, Jose Monroy Trujillo, Derek Fine, Robert Clancy, H. Michael Belmont, Peter Izmirly, William Apruzzese, Daniel Goldman, Celine C. Berthier, Paul Hoover, Nir Hacohen, Soumya Raychaudhuri, Anne Davidson, Betty Diamond, the Accelerating Medicines Partnership in RA/SLE network, Michelle Petri